DESCRIPTION: (Applicant's Abstract) The purpose of this program project is to elucidate the pharmacological and structural-conformational properties of dynorphin-derived peptides that mediate nonopioid effects that may be important in understanding drug abuse. These effects include 1) reversal of morphine tolerance and restoration of spinal-supraspinal synergism of opioid receptors (Lee); 2) inhibition of sensitization to cocaine (Dworkin/Shippenberg); and 3) stimulation of ACTH release from fetal pituitary (Szeto). The nonopioid nature of these effects is demonstrated by a) their insensitivity to opioid antagonists such as naloxone and nor-BNI; b) their mediation by dynorphinA-(2-17), which does not bind to opioid receptors. However, each of these systems also manifests involvement of opioid receptors, suggesting that dynorphin may play a dual regulatory role in each, acting through both opioid and nonopioid receptors. The nonopioid system(s) mediating these effects of dynorphin have proven extremely complex, necessitating an integrated approach in which pharmacological data are used to inform structural-conformational studies that are aimed at defining the critical features of the dynorphin peptide required for interacting with the(se) non-opioid receptor or receptors (Weinstein). Insight into structural requirements will also be provided by studies of dynorphin peptides present endogenously (Hook), which might function as ligands for the nonopioid receptor(s). The data obtained from this multidisciplinary collaboration will define the nonopioid dynorphin system and enable the program to move on to a second phase in which the receptors will be cloned and expressed.